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1.
Nutrients ; 13(8)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445051

RESUMO

Intrauterine growth restriction (IUGR) is associated with reduced placental amino acid transport (AAT). However, it remains to be established if changes in AAT contribute to restricted fetal growth. We hypothesized that reduced in vivo placental AAT precedes the development of IUGR in baboons with maternal nutrient restriction (MNR). Baboons were fed either a control (ad libitum) or MNR diet (70% of control diet) from gestational day (GD) 30. At GD 140, in vivo transplacental AA transport was measured by infusing nine (13)C- or (2)H-labeled essential amino acids (EAAs) as a bolus into the maternal circulation at cesarean section. A fetal vein-to-maternal artery mole percent excess ratio for each EAA was measured. Microvillous plasma membrane (MVM) system A and system L transport activity were determined. Fetal and placental weights were not significantly different between MNR and control. In vivo, the fetal vein-to-maternal artery mole percent excess ratio was significantly decreased for tryptophan in MNR. MVM system A and system L activity was markedly reduced in MNR. Reduction of in vivo placental amino acid transport precedes fetal growth restriction in the non-human primate, suggesting that reduced placental amino acid transfer may contribute to IUGR.


Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Sistema L de Transporte de Aminoácidos/metabolismo , Aminoácidos/metabolismo , Dieta com Restrição de Proteínas , Retardo do Crescimento Fetal/etiologia , Troca Materno-Fetal , Placenta/metabolismo , Animais , Transporte Biológico , Modelos Animais de Doenças , Feminino , Desenvolvimento Fetal , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/fisiopatologia , Idade Gestacional , Fenômenos Fisiológicos da Nutrição Materna , Papio , Gravidez
2.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360913

RESUMO

Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measurements were assessed by Doppler ultrasonography. At 120 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies with the 3H2O transplacental diffusion technique at 130 dGA. Nutrient uptake rates were determined and tissues were subsequently harvested at necropsy. CSH RNAi reduced (p ≤ 0.05) both fetal and uterine weights as well as umbilical blood flow (mL/min). This ultimately resulted in reduced (p ≤ 0.01) umbilical IGF1 concentrations, as well as reduced umbilical nutrient uptakes (p ≤ 0.05) in CSH RNAi pregnancies. CSH RNAi also reduced (p ≤ 0.05) uterine nutrient uptakes as well as uteroplacental glucose utilization. These data suggest that CSH is necessary to facilitate adequate blood flow for the uptake of oxygen, oxidative substrates, and hormones essential to support fetal and uterine growth.


Assuntos
Sangue Fetal/metabolismo , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Hemodinâmica/genética , Nutrientes/metabolismo , Lactogênio Placentário/deficiência , Lactogênio Placentário/genética , Interferência de RNA , Ovinos/genética , Transdução de Sinais/genética , Animais , Blastocisto/metabolismo , Feminino , Sangue Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/diagnóstico por imagem , Feto/metabolismo , Idade Gestacional , Glucose/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Placenta/metabolismo , Gravidez , RNA Interferente Pequeno/genética , Ultrassonografia Doppler/métodos , Útero/metabolismo
3.
FASEB J ; 35(9): e21788, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34425031

RESUMO

Hypoxia increases fetal hepatic insulin-like growth factor binding protein-1 (IGFBP-1) phosphorylation mediated by mechanistic target of rapamycin (mTOR) inhibition. Whether maternal nutrient restriction (MNR) causes fetal hypoxia remains unclear. We used fetal liver from a baboon (Papio sp.) model of intrauterine growth restriction due to MNR (70% global diet of Control) and liver hepatocellular carcinoma (HepG2) cells as a model for human fetal hepatocytes and tested the hypothesis that mTOR-mediated IGFBP-1 hyperphosphorylation in response to hypoxia requires hypoxia-inducible factor-1α (HIF-1α) and regulated in development and DNA-damage responses-1 (REDD-1) signaling. Western blotting (n = 6) and immunohistochemistry (n = 3) using fetal liver indicated greater expression of HIF-1α, REDD-1 as well as erythropoietin and its receptor, and vascular endothelial growth factor at GD120 (GD185 term) in MNR versus Control. Moreover, treatment of HepG2 cells with hypoxia (1% pO2 ) (n = 3) induced REDD-1, inhibited mTOR complex-1 (mTORC1) activity and increased IGFBP-1 secretion/phosphorylation (Ser101/Ser119/Ser169). HIF-1α inhibition by echinomycin or small interfering RNA silencing prevented the hypoxia-mediated inhibition of mTORC1 and induction of IGFBP-1 secretion/phosphorylation. dimethyloxaloylglycine (DMOG) induced HIF-1α and also REDD-1 expression, inhibited mTORC1 and increased IGFBP-1 secretion/phosphorylation. Induction of HIF-1α (DMOG) and REDD-1 by Compound 3 inhibited mTORC1, increased IGFBP-1 secretion/ phosphorylation and protein kinase PKCα expression. Together, our data demonstrate that HIF-1α induction, increased REDD-1 expression and mTORC1 inhibition represent the mechanistic link between hypoxia and increased IGFBP-1 secretion/phosphorylation. We propose that maternal undernutrition limits fetal oxygen delivery, as demonstrated by increased fetal liver expression of hypoxia-responsive proteins in baboon MNR. These findings have important implications for our understanding of the pathophysiology of restricted fetal growth.


Assuntos
Técnicas de Cultura de Células , Modelos Animais de Doenças , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Hipóxia/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Animais , Eritropoetina/metabolismo , Peso Fetal , Feto/química , Células Hep G2 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas In Vitro , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/química , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Microscopia de Fluorescência , Tamanho do Órgão , Papio , Fosforilação , Proteína Quinase C-alfa/metabolismo , Receptores da Eritropoetina/metabolismo , Fatores de Transcrição/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Am J Physiol Regul Integr Comp Physiol ; 321(3): R352-R363, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34287074

RESUMO

Fetal skeletal muscle growth requires myoblast proliferation, differentiation, and fusion into myofibers in addition to protein accretion for fiber hypertrophy. Oxygen is an important regulator of this process. Therefore, we hypothesized that fetal anemic hypoxemia would inhibit skeletal muscle growth. Studies were performed in late-gestation fetal sheep that were bled to anemic and therefore hypoxemic conditions beginning at ∼125 days of gestation (term = 148 days) for 9 ± 0 days (n = 19) and compared with control fetuses (n = 16). A metabolic study was performed on gestational day ∼134 to measure fetal protein kinetic rates. Myoblast proliferation and myofiber area were determined in biceps femoris (BF), tibialis anterior (TA), and flexor digitorum superficialis (FDS) muscles. mRNA expression of muscle regulatory factors was determined in BF. Fetal arterial hematocrit and oxygen content were 28% and 52% lower, respectively, in anemic fetuses. Fetal weight and whole body protein synthesis, breakdown, and accretion rates were not different between groups. Hindlimb length, however, was 7% shorter in anemic fetuses. TA and FDS muscles weighed less, and FDS myofiber area was smaller in anemic fetuses compared with controls. The percentage of Pax7+ myoblasts that expressed Ki67 was lower in BF and tended to be lower in FDS from anemic fetuses indicating reduced myoblast proliferation. There was less MYOD and MYF6 mRNA expression in anemic versus control BF consistent with reduced myoblast differentiation. These results indicate that fetal anemic hypoxemia reduced muscle growth. We speculate that fetal muscle growth may be improved by strategies that increase oxygen availability.


Assuntos
Proliferação de Células/fisiologia , Desenvolvimento Fetal/fisiologia , Hipóxia/metabolismo , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Animais , Feminino , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Membro Posterior/metabolismo , Desenvolvimento Muscular/fisiologia , Ovinos
5.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281280

RESUMO

Cold shock Y-box binding protein-1 (YB-1) coordinates several molecular processes between the nucleus and the cytoplasm and plays a crucial role in cell function. Moreover, it is involved in cancer progression, invasion, and metastasis. As trophoblast cells share similar characteristics with cancer cells, we hypothesized that YB-1 might also be necessary for trophoblast functionality. In samples of patients with intrauterine growth restriction, YB-1 mRNA levels were decreased, while they were increased in preeclampsia and unchanged in spontaneous abortions when compared to normal pregnant controls. Studies with overexpression and downregulation of YB-1 were performed to assess the key trophoblast processes in two trophoblast cell lines HTR8/SVneo and JEG3. Overexpression of YB-1 or exposure of trophoblast cells to recombinant YB-1 caused enhanced proliferation, while knockdown of YB-1 lead to proliferative disadvantage in JEG3 or HTR8/SVneo cells. The invasion and migration properties were affected at different degrees among the trophoblast cell lines. Trophoblast expression of genes mediating migration, invasion, apoptosis, and inflammation was altered upon YB-1 downregulation. Moreover, IL-6 secretion was excessively increased in HTR8/SVneo. Ultimately, YB-1 directly binds to NF-κB enhancer mark in HTR8/SVneo cells. Our data show that YB-1 protein is important for trophoblast cell functioning and, when downregulated, leads to trophoblast disadvantage that at least in part is mediated by NF-κB.


Assuntos
Complicações na Gravidez/metabolismo , Trofoblastos/metabolismo , Aborto Espontâneo/genética , Aborto Espontâneo/metabolismo , Aborto Espontâneo/patologia , Adulto , Apoptose , Estudos de Casos e Controles , Linhagem Celular , Movimento Celular , Proliferação de Células , Regulação para Baixo , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Técnicas de Silenciamento de Genes , Humanos , Técnicas In Vitro , Masculino , NF-kappa B/metabolismo , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Trofoblastos/patologia , Regulação para Cima , Proteína 1 de Ligação a Y-Box/antagonistas & inibidores , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo , Adulto Jovem
6.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209700

RESUMO

Disruption of the in utero environment can have dire consequences on fetal growth and development. Intrauterine growth restriction (IUGR) is a pathological condition by which the fetus deviates from its expected growth trajectory, resulting in low birth weight and impaired organ function. The developmental origins of health and disease (DOHaD) postulates that IUGR has lifelong consequences on offspring well-being, as human studies have established an inverse relationship between birth weight and long-term metabolic health. While these trends are apparent in epidemiological data, animal studies have been essential in defining the molecular mechanisms that contribute to this relationship. One such mechanism is cellular stress, a prominent underlying cause of the metabolic syndrome. As such, this review considers the role of oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and inflammation in the pathogenesis of metabolic disease in IUGR offspring. In addition, we summarize how uncontrolled cellular stress can lead to programmed cell death within the metabolic organs of IUGR offspring.


Assuntos
Suscetibilidade a Doenças , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/metabolismo , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Estresse Fisiológico , Animais , Apoptose , Biomarcadores , Estresse do Retículo Endoplasmático , Retardo do Crescimento Fetal/diagnóstico , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/etiologia , Doenças do Recém-Nascido/metabolismo , Síndrome Metabólica/diagnóstico , Modelos Biológicos , Fosforilação Oxidativa , Estresse Oxidativo , Resposta a Proteínas não Dobradas
7.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299087

RESUMO

Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24-34 weeks' (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (<34 weeks) delivery. Using first-trimester human trophoblast stem cells, SPINT2 expression was assessed in hypoxia/normoxia (1% vs. 8% O2), and following inflammatory cytokine treatment (TNFα, IL-6). Placental SPINT2 mRNA was measured in a rat model of late-gestational foetal growth restriction. At 36 weeks, circulating SPINT2 was elevated in patients who later developed preeclampsia (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency.


Assuntos
Biomarcadores/metabolismo , Retardo do Crescimento Fetal/diagnóstico , Glicoproteínas de Membrana/metabolismo , Doenças Placentárias/diagnóstico , Placenta/patologia , Pré-Eclâmpsia/diagnóstico , Trofoblastos/patologia , Adolescente , Feminino , Retardo do Crescimento Fetal/metabolismo , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Estudos Longitudinais , Placenta/metabolismo , Doenças Placentárias/metabolismo , Pré-Eclâmpsia/metabolismo , Gravidez , Estudos Prospectivos , Trofoblastos/metabolismo
8.
J Anim Sci ; 99(7)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34107017

RESUMO

Few studies have focused on the role of dimethylglycine sodium (DMG-Na) salt in protecting the redox status of skeletal muscle, although it is reported to be beneficial in animal husbandry. This study investigated the beneficial effects of DMG-Na salt on the growth performance, longissimus dorsi muscle (LM) redox status, and mitochondrial function in weaning piglets that were intrauterine growth restricted (IUGR). Ten normal birth weight (NBW) newborn piglets (1.53 ± 0.04 kg) and 20 IUGR newborn piglets (0.76 ± 0.06 kg) from 10 sows were obtained. All piglets were weaned at 21 d of age and allocated to the three groups with 10 replicates per group: NBW weaned piglets fed a common basal diet (N); IUGR weaned piglets fed a common basal diet (I); IUGR weaned piglets fed a common basal diet supplemented with 0.1% DMG-Na (ID). They were slaughtered at 49 d of age to collect the serum and LM samples. Compared with the N group, the growth performance, LM structure, serum, and, within the LM, mitochondrial redox status, mitochondrial respiratory chain complex activity, energy metabolites, redox status-related, cell adhesion-related, and mitochondrial function-related gene expression, and protein expression deteriorated in group I (P < 0.05). The ID group showed improved growth performance, LM structure, serum, and, within the LM, mitochondrial redox status, mitochondrial respiratory chain complex activity, energy metabolites, redox status-related, cell adhesion-related, and mitochondrial function-related gene expression, and protein expression compared with those in the I group (P < 0.05). The above results indicated that the DMG-Na salt treatment could improve the LM redox status and mitochondrial function in IUGR weaned piglets via the nuclear factor erythroid 2-related factor 2/sirtuin 1/peroxisome proliferator-activated receptorγcoactivator-1α network, thus improving their growth performance.


Assuntos
DNA Mitocondrial , Doenças dos Suínos , Animais , Suplementos Nutricionais , Feminino , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/veterinária , Músculo Esquelético/metabolismo , Oxirredução , Sarcosina/análogos & derivados , Sódio , Suínos , Doenças dos Suínos/metabolismo , Desmame
9.
Am J Physiol Lung Cell Mol Physiol ; 321(3): L545-L552, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34159801

RESUMO

Intrauterine growth restriction (IUGR) increases the risk of bronchopulmonary dysplasia (BPD), one of the major complications of prematurity. Antenatal low-protein diet (LPD) exposure in rats induces IUGR and mimics BPD-related alveolarization disorders. Peroxisome proliferator-activated receptor-γ (PPARγ) plays a key role in normal lung development and was found deregulated following LPD exposure. The objective of this article was to investigate the effects of nebulized curcumin, a natural PPARγ agonist, to prevent IUGR-related abnormal lung development. We studied rat pups antenatally exposed to an LPD or control diet (CTL) and treated with nebulized curcumin (50 mg/kg) or vehicle from postnatal (P) days 1 to 5. The primary readouts were lung morphometric analyses at P21. Immunohistochemistry (P21) and microarrays (P6 and P11) were compared within animals exposed to LPD versus controls, with and without curcumin treatment. Quantitative morphometric analyses revealed that LPD induced abnormal alveolarization as evidenced by a significant increase in mean linear intercept (MLI) observed in P21 LPD-exposed animals. Early curcumin treatment prevented this effect, and two-way ANOVA analysis demonstrated significant interaction between diet and curcumin both for MLI [F(1,39) = 12.67, P = 0.001] and radial alveolar count at P21 [F(1,40) = 6.065, P = 0.0182]. Immunohistochemistry for fatty acid binding protein 4 (FABP4), a major regulator of PPARγ pathway, showed a decreased FABP4+ alveolar cell density in LPD-exposed animals treated by curcumin. Transcriptomic analysis showed that early curcumin significantly prevented the activation of profibrotic pathways observed at P11 in LPD-exposed animals. Nebulized curcumin appears to be a promising strategy to prevent alveolarization disorders in IUGR rat pups, targeting pathways involved in lung development.


Assuntos
Displasia Broncopulmonar/prevenção & controle , Curcumina/farmacologia , Dieta com Restrição de Proteínas/efeitos adversos , Alvéolos Pulmonares/metabolismo , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patologia , Feminino , Retardo do Crescimento Fetal/tratamento farmacológico , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Masculino , Nebulizadores e Vaporizadores , PPAR gama/agonistas , PPAR gama/metabolismo , Alvéolos Pulmonares/patologia , Ratos , Ratos Sprague-Dawley
10.
Am J Physiol Regul Integr Comp Physiol ; 321(2): R112-R124, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075808

RESUMO

Preeclampsia (PE) is characterized by maternal hypertension, intrauterine growth restriction, and increased cytolytic natural killer cells (cNKs), which secrete interferon γ (IFNγ). However, the precise role of IFNγ in contributing to PE pathophysiology remains unclear. Using the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia, we tested the hypothesis that neutralization of IFNγ in RUPPs will decrease placental reactive oxygen species (ROS) and improve vascular function resulting in decreased MAP and improved fetal growth. On gestation day (GD) 14, the RUPP procedure was performed and on GDs 15 and 18, a subset of normal pregnant rats (NP) and RUPP rats were injected with 10 µg/kg of an anti-rat IFNγ monoclonal antibody. On GD 18, uterine artery resistance index (UARI) was measured via Doppler ultrasound and on GD 19, mean arterial pressure (MAP) was measured, animals were euthanized, and blood and tissues were collected for analysis. Increased MAP was observed in RUPP rats compared with NP and was reduced in RUPP + anti-IFNγ. Placental ROS was also increased in RUPP rats compared with NP rats and was normalized in RUPP + anti-IFNγ. Fetal and placental weights were reduced in RUPP rats, but were not improved following anti-IFNγ treatment. However, UARI was elevated in RUPP compared with NP rats and was reduced in RUPP + anti-IFNγ. In conclusion, we observed that IFNγ neutralization reduced MAP, UARI, and placental ROS in RUPP recipients. These data suggest that IFNγ is a potential mechanism by which cNKs contribute to PE pathophysiology and may represent a therapeutic target to improve maternal outcomes in PE.


Assuntos
Anticorpos Monoclonais/farmacologia , Pressão Arterial/efeitos dos fármacos , Interferon gama/antagonistas & inibidores , Células Matadoras Naturais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Placenta/irrigação sanguínea , Placenta/efeitos dos fármacos , Pré-Eclâmpsia/prevenção & controle , Artéria Uterina/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Proteínas Angiogênicas/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/fisiopatologia , Retardo do Crescimento Fetal/prevenção & controle , Interferon gama/metabolismo , Isquemia/metabolismo , Isquemia/fisiopatologia , Células Matadoras Naturais/metabolismo , Placenta/metabolismo , Circulação Placentária , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Artéria Uterina/metabolismo , Artéria Uterina/fisiopatologia
11.
Obstet Gynecol Clin North Am ; 48(2): 247-266, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33972064

RESUMO

Placental regulation of fetal growth involves the integration of multiple signaling pathways that modulate an array of placental functions, including nutrient transport. As a result, the flux of oxygen and nutrients to the fetus is altered, leading to changes in placental and fetal growth. Placental insulin/insulinlike growth factor-1 and mechanistic target of rapamycin signaling and amino acid transport capacity are inhibited in fetal growth restriction and activated in fetal overgrowth, implicating these placental functions in driving fetal growth. With novel approaches to specifically target the placenta, clinical interventions to modulate placental function in high-risk pregnancies can be developed.


Assuntos
Desenvolvimento Fetal , Retardo do Crescimento Fetal/metabolismo , Macrossomia Fetal/metabolismo , Placenta/metabolismo , Adiponectina/metabolismo , Animais , Diabetes Gestacional/epidemiologia , Feminino , Humanos , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Troca Materno-Fetal , Gravidez , Proteínas da Gravidez/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Trofoblastos/metabolismo
12.
Am J Physiol Renal Physiol ; 321(1): F93-F105, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34056927

RESUMO

Intrauterine growth restriction (IUGR) due to an adverse intrauterine environment predisposes to arterial hypertension and loss of kidney function. Here, we investigated whether vascular dysregulation in renal interlobar arteries (RIAs) may contribute to hypertensive glomerular damage after IUGR. In rats, IUGR was induced by bilateral uterine vessel ligation. Offspring of nonoperated rats served as controls. From postnatal day 49, blood pressure was telemetrically recorded. On postnatal day 70, we evaluated contractile function in RIAs and mesenteric arteries. In addition, blood, urine, and glomerular parameters as well as renal collagen deposition were analyzed. IUGR RIAs not only showed loss of stretch activation in 9 of 11 arteries and reduced stretch-induced myogenic tone but also showed a shift of the concentration-response relation of acetylcholine-induced relaxation toward lower concentrations. However, IUGR RIAs also exhibited augmented contractions through phenylephrine. Systemic mean arterial pressure [mean difference: 4.8 mmHg (daytime) and 5.7 mmHg (night)], mean glomerular area (IUGR: 9,754 ± 338 µm2 and control: 8,395 ± 227 µm2), and urinary protein-to-creatinine ratio (IUGR: 1.67 ± 0.13 g/g and control: 1.26 ± 0.10 g/g) were elevated after IUGR. We conclude that male IUGR rat offspring may have increased vulnerability toward hypertensive glomerular damage due to loss of myogenic tone and augmented endothelium-dependent relaxation in RIAs.NEW & NOTEWORTHY For the first time, our study presents wire myography data from renal interlobar arteries (RIAs) and mesenteric arteries of young adult rat offspring after intrauterine growth restriction (IUGR). Our data indicate that myogenic tone in RIAs is dysfunctional after IUGR. Furthermore, IUGR offspring suffer from mild arterial hypertension, glomerular hypertrophy, and increased urinary protein-to-creatinine ratio. Dysregulation of vascular tone in RIAs could be an important variable that impacts upon vulnerability toward glomerular injury after IUGR.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Hipertensão/fisiopatologia , Rim/metabolismo , Artéria Renal/fisiopatologia , Animais , Pressão Sanguínea/fisiologia , Retardo do Crescimento Fetal/fisiopatologia , Rim/efeitos dos fármacos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Fenilefrina/farmacologia , Ratos
13.
Ann Clin Lab Sci ; 51(2): 182-189, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33941557

RESUMO

OBJECTIVE: Fetal growth restriction (FGR) refers to impaired and insufficient intrauterine growth potential caused by a variety of adverse factors and is a serious perinatal complication that leads to fetal or neonatal mortality and morbidity. FGR has numerous causes, and its pathogenesis has not been fully understood. Recently, increasing numbers of researchers have begun to focus on the placenta, the only link between the fetus and the mother. The placenta is a vital organ that plays key roles in fetal development. PLAC1 is a trophoblast-specific gene located on the X chromosome and is important for placental development. However, the biological role of PLAC1 in fetal growth restriction is not well understood. In this study, we investigated the changes in the expression of placental-specific protein 1(PLAC1) in the placentas of pregnant women with FGR and in the placentas of normal pregnancies. We also explored the regulation of PLAC1 in the growth of trophoblast cells. METHODS: Western blotting was used to detect the expression of PLAC1 in FGR and in normal placenta tissues. Cell counting kit 8 (CCK-8), wound healing, and transwell assays were used to detect the effects of PLAC1 knockdown on trophoblast cell proliferation, migration, and invasion. Western blotting was used to detect the expression of PLAC1 under hypoxic conditions, and the cell viability and apoptosis of trophoblast cells in a low oxygen concentration after overexpression of PLAC1 were detected by CCK-8 and flow cytometry assay. RESULTS: Compared with the placentas in the control group of normal pregnancies, the expression of PLAC1 in the placentas of the FGR group was significantly down-regulated (p<0.05). Knocking down PLAC1 by siRNA significantly inhibited the proliferation, migration, and invasion of trophoblast cells. After treatment with alow oxygen concentration, the expression of PLAC1 protein was significantly reduced (p<0.05). The overexpression of PLAC1 can reverse the cell viability of trophoblast cells (p<0.05) and inhibit apoptosis of trophoblast cells (p<0.05) in low oxygen concentration. CONCLUSION: The expression of PLAC1 was reduced in fetal growth restriction and did not protect trophoblast cells from hypoxic damage, suggesting that PLAC1 may be an important regulator in the occurrence of fetal growth restriction.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Proteínas da Gravidez/metabolismo , Trofoblastos/metabolismo , Adulto , Apoptose/genética , Linhagem Celular , Movimento Celular/genética , Proliferação de Células/genética , China , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Placenta/metabolismo , Placenta/patologia , Gravidez , Proteínas da Gravidez/genética , Proteínas da Gravidez/fisiologia , Transdução de Sinais/genética , Trofoblastos/patologia
14.
FASEB J ; 35(5): e21477, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33891326

RESUMO

Chronic fetal hypoxia is one of the most common outcomes in complicated pregnancy in humans. Despite this, its effects on the long-term health of the brain in offspring are largely unknown. Here, we investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with maternal antioxidant intervention. Pregnant rats were randomly chosen for normoxic or hypoxic (13% oxygen) pregnancy with or without maternal supplementation with vitamin C in their drinking water. In one cohort, the placenta and fetal tissues were collected at the end of gestation. In another, dams were allowed to deliver naturally, and offspring were reared under normoxic conditions until 4 months of age (young adult). Between 3.5 and 4 months, the behavior, cognition and brains of the adult offspring were studied. We demonstrated that prenatal hypoxia reduced neuronal number, as well as vascular and synaptic density, in the hippocampus, significantly impairing memory function in the adult offspring. These adverse effects of prenatal hypoxia were independent of the hypoxic pregnancy inducing fetal growth restriction or elevations in maternal or fetal plasma glucocorticoid levels. Maternal vitamin C supplementation during hypoxic pregnancy protected against oxidative stress in the placenta and prevented the adverse effects of prenatal hypoxia on hippocampal atrophy and memory loss in the adult offspring. Therefore, these data provide a link between prenatal hypoxia, placental oxidative stress, and offspring brain health in later life, providing insight into mechanism and identifying a therapeutic strategy.


Assuntos
Ácido Ascórbico/uso terapêutico , Atrofia/tratamento farmacológico , Hipóxia Fetal/complicações , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Animais , Animais Recém-Nascidos , Antioxidantes/uso terapêutico , Atrofia/etiologia , Atrofia/metabolismo , Atrofia/patologia , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/tratamento farmacológico , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/etiologia , Complicações na Gravidez/metabolismo , Complicações na Gravidez/patologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar
15.
Saudi Med J ; 42(5): 491-498, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33896778

RESUMO

OBJECTIVES: To assess the oxidation state and gene expression profiles of relevant enzymes in intrauterine growth restriction (IUGR) patients in Saudi Arabia. METHODS: Current case-control study involved plasma and placental tissue samples from 25 IUGR patients and 25 healthy pregnant (HP) women attending the Obstetrics and Gynecology Clinic, King Khalid University Hospital, Riyadh, Saudi Arabia, between April and November 2017. We compared hydrogen peroxide, superoxide anions, malondialdehyde, and oxidative stress markers levels and the activities of glutathione-related enzymes (glutathione peroxidase [GPx], glutathione reductase [GR], glutathione S-transferase [GST], glutamate cysteine ligase [GCL], glutathione synthetase [GS], reduced glutathione [GSH], oxidized glutathione [GSSG], and oxidized nicotinamide adenine dinucleotide [NAD+], and reduced NAD [NADH]) between the 2 groups. We also compared differential expression levels of glutathione-related enzyme genes using reverse transcription-quantitative polymerase chain reaction. RESULTS: Oxidative stress markers significantly differed in IUGR samples, while GSH levels and GPx, GR, GST, GCL, and GS activities and their placental mRNA transcriptional levels were significantly lower. Plasma and placental NAD+ levels were also significantly lower, while NADH levels were significantly higher, causing lowered NAD+-NADH ratios in the IUGR group compared to control. CONCLUSIONS: Intrauterine growth restriction patients show a metabolic shift in favor of oxidation compared to HP women.


Assuntos
Glutationa , NAD , Estudos de Casos e Controles , Feminino , Retardo do Crescimento Fetal/metabolismo , Glutationa/metabolismo , Humanos , NAD/metabolismo , Oxirredução , Estresse Oxidativo , Placenta , Gravidez , Arábia Saudita
16.
Int J Mol Sci ; 22(8)2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33919502

RESUMO

Abnormally accelerated, premature placental senescence plays a crucial role in the genesis of pregnancy pathologies. Abnormal growth in the third trimester can present as small for gestational age fetuses or fetal growth restriction. One differs from the other by the presence of signs of placental insufficiency and the risk of stillbirth. The majority of stillbirths occur in normally grown fetuses and are classified as "unexplained", which often leads to conclusions that they were unpreventable. The main characteristic of aging is a gradual decline in the function of cells, tissues, and organs. These changes result in the accumulation of senescent cells in mitotic tissues. These cells begin the aging process that disrupts tissues' normal functions by affecting neighboring cells, degrading the extracellular matrix, and reducing tissues' regeneration capacity. Different degrees of abnormal placentation result in the severity of fetal growth restriction and its sequelae, including fetal death. This review aims to present the current knowledge and identify future research directions to understand better placental aging in late fetal growth restriction and unexplained stillbirth. We hypothesized that the final diagnosis of placental insufficiency can be made only using markers of placental senescence.


Assuntos
Senescência Celular/fisiologia , Retardo do Crescimento Fetal/metabolismo , Animais , Senescência Celular/genética , Feminino , Retardo do Crescimento Fetal/genética , Humanos , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Gravidez , Natimorto/genética , Homeostase do Telômero/genética , Homeostase do Telômero/fisiologia
17.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925868

RESUMO

Nitric oxide (NO) is essential in the control of fetoplacental vascular tone, maintaining a high flow-low resistance circulation that favors oxygen and nutrient delivery to the fetus. Reduced fetoplacental blood flow is associated with pregnancy complications and is one of the major causes of fetal growth restriction (FGR). The reduction of dietary nitrate to nitrite and subsequently NO may provide an alternative source of NO in vivo. We have previously shown that nitrite induces vasorelaxation in placental blood vessels from normal pregnancies, and that this effect is enhanced under conditions of hypoxia. Herein, we aimed to determine whether nitrite could also act as a vasodilator in FGR. Using wire myography, vasorelaxant effects of nitrite were assessed on pre-constricted chorionic plate arteries (CPAs) and veins (CPVs) from normal and FGR pregnancies under normoxic and hypoxic conditions. Responses to the NO donor, sodium nitroprusside (SNP), were assessed in parallel. Nitrate and nitrite concentrations were measured in fetal plasma. Hypoxia significantly enhanced vasorelaxation to nitrite in FGR CPAs (p < 0.001), and in both normal (p < 0.001) and FGR (p < 0.01) CPVs. Vasorelaxation to SNP was also potentiated by hypoxia in both normal (p < 0.0001) and FGR (p < 0.01) CPVs. However, compared to vessels from normal pregnancies, CPVs from FGR pregnancies showed significantly lower reactivity to SNP (p < 0.01). Fetal plasma concentrations of nitrate and nitrite were not different between normal and FGR pregnancies. Together, these data show that nitrite-mediated vasorelaxation is preserved in FGR, suggesting that interventions targeting this pathway have the potential to improve fetoplacental blood flow in FGR pregnancies.


Assuntos
Retardo do Crescimento Fetal , Nitritos/farmacologia , Complicações na Gravidez/metabolismo , Vasodilatação/efeitos dos fármacos , Córion , Feminino , Retardo do Crescimento Fetal/tratamento farmacológico , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Humanos , Hipóxia , Miografia/métodos , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacologia , Nitritos/metabolismo , Placenta/metabolismo , Circulação Placentária/efeitos dos fármacos , Circulação Placentária/fisiologia , Gravidez , Vasodilatadores/farmacologia
18.
Int J Mol Sci ; 22(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915805

RESUMO

Low birth weight and rapid postnatal weight gain are independent predictors of obesity and diabetes in adult life, yet the molecular events involved in this process remain unknown. In inbred and outbred mice, this study examines natural intrauterine growth restriction (IUGR) in relation to body weight, telomere length (TL), glucose tolerance, and growth factor gene (Igf1, Igf2, Insr, Igf1r, and Igf2r) mRNA expression levels in the brain, liver, and muscle at 2- and 10 days of age and then at 3- and 9 months of age. At birth, ~15% of the animals showed IUGR, but by 3 and 9 months, half of these animals had regained the same weight as controls without IUGR (recuperated group). At 10 days, there was no difference in TL between animals undergoing IUGR and controls. However, by 3 and 9 months of age, the recuperated animals had shorter TL than the control and IUGR-non recuperated animals and also showed glucose intolerance. Further, compared to controls, Igf1 and Igf2 growth factor mRNA expression was lower in Day 2-IUGR mice, while Igf2r and Insr mRNA expression was higher in D10-IUGR animals. Moreover, at 3 months of age, only in the recuperated group were brain and liver Igf1, Igf2, Insr, and Igf2r expression levels higher than in the control and IUGR-non-recuperated groups. These data indicate that catch-up growth but not IUGR per se affects TL and glucose tolerance, and suggest a role in this latter process of insulin/insulin-like growth signaling pathway gene expression during early development.


Assuntos
Peso Corporal , Retardo do Crescimento Fetal/metabolismo , Intolerância à Glucose/etiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Homeostase do Telômero , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Regulação da Expressão Gênica no Desenvolvimento , Fígado/metabolismo , Masculino , Camundongos , Músculos/metabolismo
19.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925454

RESUMO

Leptin is secreted by the placenta and has a multi-facetted role in the regulation of functions related to pregnancy. Metabolic disorders and insufficient homeostatic compensatory mechanisms involving leptin during pregnancy play a decisive role in the development of pre-eclampsia (PE) and give rise to compromised intrauterine growth conditions and aberrant birth weight of offspring. This review was compiled to elucidate the metabolic background of PE and its relationship with adverse intrauterine growth conditions through the examination of leptin as well as to describe possible mechanisms linking leptin to fetal growth restriction. This review illustrates that leptin in PE is dysregulated in maternal, fetal, and placental compartments. There is no single set of unifying mechanisms within the spectrum of PE, and regulatory mechanisms involving leptin are specific to each situation. We conclude that dysregulated leptin is involved in fetal growth at many levels through complex interactions with parallel pregnancy systems and probably throughout the entirety of pregnancy.


Assuntos
Retardo do Crescimento Fetal/etiologia , Leptina/metabolismo , Pré-Eclâmpsia/metabolismo , Animais , Feminino , Retardo do Crescimento Fetal/metabolismo , Humanos , Leptina/sangue , Leptina/fisiologia , Placenta/metabolismo , Gravidez , Receptores para Leptina/metabolismo
20.
Am J Physiol Heart Circ Physiol ; 320(5): H1923-H1934, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33739156

RESUMO

Stimulation of soluble guanylate cyclase (sGC) improves fetal growth at gestational day 20 in the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia suggesting a role for sGC in the etiology of intrauterine growth restriction (IUGR). This study tested the hypothesis that stimulation of sGC until birth attenuates asymmetric IUGR mitigating increased cardiovascular risk in offspring. Sham or RUPP surgery was performed at gestational day 14 (G14); vehicle or the sGC stimulator Riociguat (10 mg/kg/day sc) was administered G14 until birth. Birth weight was reduced in offspring from RUPP [intrauterine growth restricted (IUGR)], sGC RUPP (sGC IUGR), and sGC Sham (sGC Control) compared with Sham (Control). Crown circumference was maintained, but abdominal circumference was reduced in IUGR and sGC IUGR compared with Control indicative of asymmetrical growth. Gestational length was prolonged in sGC RUPP, and survival at birth was reduced in sGC IUGR. Probability of survival to postnatal day 2 was also significantly reduced in IUGR and sGC IUGR versus Control and in sGC IUGR versus IUGR. At 4 mo of age, blood pressure was increased in male IUGR and sGC IUGR but not male sGC Control born with symmetrical IUGR. Global longitudinal strain was increased and stroke volume was decreased in male IUGR and sGC IUGR compared with Control. Thus late gestational stimulation of sGC does not mitigate asymmetric IUGR or increased cardiovascular risk in male sGC IUGR. Furthermore, late gestational stimulation of sGC is associated with symmetrical growth restriction in sGC Control implicating contraindications in normal pregnancy.NEW & NOTEWORTHY The importance of the soluble guanylate cyclase-cGMP pathway in a rat model of placental ischemia differs during critical windows of development, implicating other factors may be critical mediators of impaired fetal growth in the final stages of gestation. Moreover, increased blood pressure at 4 mo of age in male intrauterine growth restriction offspring is associated with impaired cardiac function including an increase in global longitudinal strain in conjunction with a decrease in stroke volume, ejection fraction, and cardiac output.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Placenta/irrigação sanguínea , Insuficiência Placentária/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Animais , Pressão Sanguínea/fisiologia , Ativadores de Enzimas/farmacologia , Feminino , Retardo do Crescimento Fetal/etiologia , Gravidez , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Resistência Vascular/fisiologia
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